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Former President of the Philippines Ramon Magsaysay was the first to envision a Science High School in the Philippines in his 1956 State of the Nation Address where he underscored "the great need of stepping up the development of fundamental and applied research in science and technology which has long been neglected."

Taking action, the Philippine Congress passed Republic Act 1606[1] creating the National Science Development Board to work with the Science Foundation of the Philippines in advancing scientific and technological research. This was closely followed by Republic Act 2067,[2] known as the Science Act of 1958 which proposed to integrate, coordinate, and intensify scientific and technological research and development to foster invention.

In conjunction, the Department of Education implemented RA 1606 by issuing Department Orders 1 and 5, series of 1958, for the launching of Science Talent Research.

November 25, 1959 marked the evolution of the pilot science high school in the Philippines. With 36 students screened through a competitive examination, this nucleus of a science high school had its beginnings in a single-storey building in Intramuros. On its second year, this nucleus was called the Special Science Class. March 28, 1963, witnessed each of the 32 graduates of the Special Science Class receive a gold medal. It is the first time in the history of Philippine education wherein each member of the graduating class is a gold medalist.

On October 1, 1963, the Manila Science High School was born by virtue of Municipal Resolution 426 signed by Mayor Antonio J. Villegas. Credit for the school's early success goes to then Manila High School Principal Augusto Alzona – the "Father of Manila Science High School". Modeled after the Bronx High School of Science, the special science curriculum is designed to meet the needs of scholars gifted in science and mathematics. However, opportunities, training, and experiences in varied fields are also available.

After five years in Intramuros, the Manila Science High School moved to its present site in 1966(?) with its first principal, Mr. Honesto Valdez (1963–1977). By 1977, Phase I of the Main Building was completed while the construction of Phase II was ongoing.

In September 1977, Mrs. Evelina P. Barotilla (1977–1988), the second principal, saw the completion of the Manila Science High School Complex and the renovation of the H.A. Bordner Building. The Home Economics Building was built in 1980. The whole construction project was financed by the Special Education Fund under the chairmanship of Dr. Josefina Navarro, Superintendent of City Schools, Manila.

The construction of the Php 7.5 million Technology Creativity Laboratory began in 1998 during the administration of Mrs. Daisy H. Banta, (1988–2000), third principal. The project was made possible by the Special Education Fund through the joint efforts of Mayors Gemiliano Lopez and Alfredo Lim, together with DECS-Manila Superintendent, Dr. Erlinda G. Lolarga.

The new millennium ushered in the arrival of Mrs. Susan A. Yano, fourth principal, the completion of the Antonio Maceda Building and the revival of the Manila Science High School Alumni Association. Mrs. Susan A. Yano opted for an early retirement. Ms. Edna P. Parcon, Math Department Head III, was then assigned Officer-in-Charge from July 18, 2002 to January 13, 2003, together with Ms. Betty de la Cruz, Science Supervisor, assigned Supervisor-in-Charge from October 13, 2002 to January 13, 2003.[3] Mrs. Rosita C. Herson became the principal in 2003 until 2006. After that, the Manila Science High School was under the leadership of Mrs. Salud S. Sabado from 2006 until November 15, 2008.[4]

Manila Science has been under the leadership of Mrs. Flora A. Valdez for less than a year until her retirement on January 21, 2010. Before the retirement, a government project has started: the construction of the Amadome by Manila 5th District Congressman Amado Bagatsing, which is now completed in time for the new school year and has been formally inaugurated and turned over by Cong. Bagatsing on September 8, 2010.

Due to implementing laws for the May 2010 polls,[5] Manila Science will not have a principal yet until such time that the elected Mayor of Manila appoints new school administrators. The school, at the last half of SY 2009-2010 and on the first quarter of SY 2010-2011, was under the leadership of Ms. Edna P. Parcon, the school's Mathematics Department Head until August 26, 2010 which welcomed the arrival of the seventh and second male principal, Mr. Fernando B. Orines.

In 2014 Mr. Orines was sent to Manuel Roxas High School and the Manila Science High School welcomed its eighth principal Mrs. Ma. Pura S. Talattad during which she promised to sustain the Tradition of Excellence. She bade farewell to MaSci on July 11, 2015.

On June 15, 2015, the school welcomed its ninth principal Ms. Maria Eva S. Nacion, a former Head of the school's Science Department. She also said that in her term as the Principal of Manila Science High School, she will maintain the Tradition of Excellence.